This proposal describes a 5 year career development plan for Dr. Edward B. Lee to serve as a transition to successful independent physician-scientist. Dr. Lee has completed his clinical training in Anatomic Pathology and Neuropathology at the University of Pennsylvania, and will now foster a collaborative research project with the resources of both Endocrinology and Neuropathology. This project will provide superb training for Dr. Lee to develop into an independent physician-scientist. The project will be mentored Dr. Rexford S. Ahima of the Institute for Diabetes, Obesity and Metabolism, and co-mentored by Dr. John Q. Trojanowski, Director of the Alzheimer's Disease Core Center and the Institute on Aging. This grant will provide the protected time so that Dr. Lee will gain expertise in metabolism research with formal coursework and numerous scientific seminars and meetings. The environment at the University of Pennsylvania provides the unique opportunity to parlay its expertise in aging, metabolic disorders and neurodegenerative diseases to conduct the proposed projects, and to provide Dr. Lee with the training required to proceed towards a successful academic career. Aging and obesity are both affecting the American population at record levels, and both aging and obesity are risk factors for Alzheimer's disease (AD). Although, it is known that mid-life obesity increases the risk of AD and that diet-induced obesity promotes amyloid deposition in transgenic mouse models, there is little mechanistic insight into how obesity adversely affects the aging brain. Leptin is a hormone secreted by adipose tissue with profound effects on metabolism by acting on the brain. Leptin levels are increased due to aging and obesity, and both conditions results in central leptin resistance. Leptin inhibits cerebral amyloid in transgenic mouse models, but our understanding of this effect is hampered in part because leptin has both direct effects on neuronal signaling pathways and indirect effects on metabolism. The hypothesis of this proposal is that leptin triggers neuronal signaling pathways which protect against cerebral amyloid pathology. The direct effects of leptin are difficult to ascertain in mouse models of leptin deficiency due to the numerous secondary metabolic effects which complicate interpretation including obesity, diabetes, hyperlipidemia and neuroendocrine dysfunction. To circumvent this issue, Dr. Lee will perform innovative studies to determine leptin's effects controlling for major shifts in body weight. Transgenic mice that develop cerebral amyloid will be treated with physiologic doses of leptin controlling for changes in body weight. Second, the effects of acute leptin treatment on downstream signaling pathways and A2 amyloid peptide levels will be assessed in live animals. Finally, the behavioral and pathologic effects of a leptin receptor mutation which enhances leptin receptor signaling will be determined. These studies will provide mechanistic insights into the role of leptin in AD pathogenesis, and provide the basis for future drug or biomarker development.